1. Technical Field of the Invention
The present invention relates to the formulation of at least one compound of the family of the avermectins or of the family of the milbemycins into pharmaceutical compositions useful for the treatment of ophthalmic pathologies, including ocular rosacea.
2. Description of Background And/Or Related And/Or Prior Art
Ocular rosacea is frequently diagnosed when it coexists with cutaneous signs or symptoms of rosacea (Browning D. J. and Proia A. D., Ocular Rosacea, Surv. Ophthalmol., 1986, 31, 145-58). Ocular rosacea is independent of the severity of rosacea of the skin (Donshik P. C., Floss D. M. and Ehlers W. H., Inflammatory and papulosquamous disorders of the skin and eye, Dermatologic Clinics, 1992, 3, 533-47).
In the event of ocular attack, certain studies show more women affected than men, whereas there is no significant difference according to sex for rosacea of the skin (Ramelet A. A., Rosacea: a reaction pattern associated with ocular lesions and headache, Arch. Dermatol., 1994, 130, 1448).
For a proportion of patients affected by ocular rosacea ranging up to 20%, the ocular signs and symptoms can occur before the cutaneous manifestations. The relevant symptoms for the diagnosis of ocular rosacea are as follows: feeling of burning or of smarting, feeling of a foreign body, feeling of dryness of the eye, increased sensitivity to light, blurred vision. The least serious clinical signs in patients affected by ocular rosacea are telangiectasia of the eyelid margin, meibomitis, chalazia, conjunctival hyperaemia and papillary conjunctivitis (Donshik P. C., Hoss D. M. and Ehlers W. H., Inflammatory and papulosquamous disorders of the skin and eye, Dermatologic Clinics, 1992, 3, 533-47). Dryness of the eye with quantitative deficiency of tears and bacterial superinfection frequently exist.
More serious are the problems posed by attacks on the cornea in the form of superficial punctuate keratitis and interstitial keratitis, which can develop into a decrease in visual acuity, ulceration or perforation (Jenkins M. S., Brown S. I., Lempert S. L. and Weinberg R. J., Ocular Rosacea, Am. J. Ophthalmol., 1979, 88, 618-22).
The causes of the ocular pathologies indicated above include, in particular, the presence of various organisms, such as Demodex folliculorum, the commonest human ectoparasite. However, not all ocular pathologies are related to the presence of this ectoparasite.
If ocular rosacea, which is included among ophthalmic pathologies, is not treated, serious complications may occur in the cornea and this can detrimentally affect the vision.
The therapeutic measures commonly employed are the application of hot compresses and of topical antibiotics, such as a metronidazole gel, for example. A marked improvement is obtained but is often followed by a relapse in the form of conjunctivitis.
Oral antibiotics, such as tetracycline hydrochloride or doxycycline, can also be administered. However, the level of relapse is on the order of 66% after treatment for 6 months (Zug K. A., Palay D. A. and Rock B., Dermatologic diagnosis and treatment of itchy red eyelids, Surv. Ophthalmol., 1996, 40, 293-306). A maintenance treatment is often necessary, sometimes for several years, indeed even for life. Cyclines have an anti-inflammatory action but do not have a curative action. The longer the treatment, the more there exists a risk of appearance of resistance (Quaterman M. J., Johnson D. W., Abele D. C., Lesher J. L., Hull D. S. and Davis L. S., Ocular Rosacea, Arch. Dermatol., 1997, 133, 49-54). A loss in the anti-inflammatory effectiveness is possible during long-term treatments, hence the interest in short cures (over 1 to 2 months). This treatment is used in first application, during severe attacks on the eyes, due to the risk of after-effects on the eyes.
An antibiotic of the class of the macrolides (erythromycin) can also be administered but the response to the treatment is not systematic.
Furthermore, patients suffering from ocular rosacea must not take isotretinoin, as this substance aggravates ophthalmic symptoms (Michel J. L., Valanconny C., Gain P., Montelimard N., Tchaplyguine F. and Cambazard F., Manifestations oculaires des rétinoïdes [Ocular manifestations of retinoids], Ann. Dermatol. Venereol., 1998, 125, 438-42).
None of these treatments makes possible complete and lasting remission of ocular rosacea. In view of the above, there thus exists a need to formulate a composition which shows an improved effectiveness in the treatment of ocular rosacea and which does not exhibit the side effects described in the prior art.
Ivermectin is a mixture of two compounds belonging to the class of the avermectins, 5-O-demethyl-22,23-dihydroavermectin A1a and 5-O-demethyl-22,23-dihydroavermectin A1b. They are also known under the names of 22,23-dihydroavermectin B1a and 22,23-dihydroavermectin B1b. Ivermectin comprises at least 80% of 22,23-dihydroavermectin B1a and less than 20% of 22,23-dihydroavermectin B1b. This active agent forms part of the class of the avermectins, a group of macrocyclic lactones produced by the bacterium Streptomyces avermitilis (Reynolds J. E. F. (Ed), (1993) Martindale, The Extra Pharmacopoeia, 29th Edition, Pharmaceutical Press, London).
In the mid-1980s, ivermectin was indicated as a broad-spectrum anti-parasitic medicament for veterinary application (Campbell W. C. et al. (1983), Ivermectin: a potent new anti-parasitic agent, Science, 221, 823-828). It is effective against the majority of common intestinal worms (except for the Teniae), the majority of the acarids and a few lice. It exhibits in particular a high affinity for the glutamate-dependent chloride channels present in the nerve and muscle cells of invertebrates. Its attachment to these channels promotes an increase in the membrane permeability to chloride ions, resulting in hyperpolarization of the nerve or muscle cell. This results in neuromuscular paralysis, which can bring about the death of certain parasites. Ivermectin also interacts with other ligand-dependent chloride channels, such as those involving the GABA (γ-aminobutyric acid) neuromediator.
Ivermectin is more particularly an anthelmintic. It is indicated in man for the treatment of onchocerciasis due to Onchocerca volvulus, of gastrointestinal strongyloidiasis (product Stromectol®) and of human scabies (Meinking T. L. et al., N. Engl. J. Med., 1995, July, 6, 331 (1), 26-30, The treatment of scabies with ivermectin) and in the treatment of microfilaraemia diagnosed or suspected in subjects affected by lymphatic filariasis due to Wuchereria bancrofti. 
Moreover, U.S. Pat. No. 6,133,310 describes the administration of invermectin topically in the treatment of rosacea of the skin, in the form of a prototype of a lotion composed of a mixture of invermectin and of water, and also indicates the possibility of a prototype of a cream composed, for its part, of the mixture of invermectin and of an excipient, such as propylene glycol or sodium lauryl sulfate, but does not describe any pharmaceutical composition as such. These mixtures are similar to experimental preparations to be applied to the skin, useful in the context of first results of a proof of concept. Specifically, the facts indicated in this patent do not suggest to one skilled in this art anything regarding the feasibility and the effectiveness of pharmaceutical compositions acceptable industrially for the treatment of ocular rosacea.